The fundamental characteristic of epithelia is cell-cell adhesion, which regulates signaling pathways involved in cell organization, migration and gene expression. Disruption of cell-cell adhesion leads to loss of epithelial cell organization, increasd cell migration, and loss of contact-inhibition of cell proliferation, which are characteristic of mny genetic diseases including cancer. Thus the RATIONALE for our work is that a deep mechanistic understanding of cell-cell adhesion will provide fundamental insights into the regulation of epithelial tissue organization in normal and disease states. Our CENTRAL HYPOTHESIS is that cell-cell adhesion maintains epithelial homeostasis by controlling cytoskeleton organization and cell migration, and sequestering key signaling proteins that regulate cell proliferation. Our LONG- TERM OBJECTIVES are organized under 2 broad themes that address KEY CHALLENGES about: A. Mechanisms involved in cadherin-mediated cell-cell adhesion, cytoskeleton organization and regulation of cell migration; and B. Response of cell-cell adhesion complexes to perturbation by mechanical strain. Based on significant results and technology development during the preceding period of support, we can now address KEY QUESTIONS about: Theme A. The regulation of ?E-catenin (A.1) and actin (A.2) dynamics during cell-cell adhesion, and the cross-talk between cadherin- and integrin-based adhesions that control the balance between cell-cell adhesion and migration (A.3); and Theme B. Upon mechanical strain and cell cycle re- entry, how ?-catenin and Yap1 are Trans located to the nucleus (B.1), the role of actomyosin activity (B.2) and kinases (B.3) in activating ?-catenin and Yap1, and the involvement of additional junction-mediated signaling pathways in cell cycle regulation (B.4). Completion of these studies will answer KEY QUESTIONS about the role of cell-cell adhesion in cytoskeleton organization and cell migration, and sequestering key signaling proteins that regulate cell proliferation. These studies address fundamental CHALLENGES in understanding the regulation of epithelial tissue organization in normal and disease states.